Axons in the central nervous system do not regenerate readily after traumatic injury because of the highly inhibitory environment of the adult central nervous system especially following injury. In addition, adult axons generally lack intrinsic growth potential and therefore cannot sustain the initial sprouting observed in some of the injured axons. Furthermore, injured axons often retract further back from where they are lesioned over time, making repair even more challenging. Therefore, combinatorial approaches will be necessary for successful anatomical regeneration and functional recovery. Many axon guidance molecules important in development are still present in the adult central nervous system after the nervous system. Still others are found re- induced after injury. Wnts are guidance cues that control pathfinding of a number of axons along the rostral-caudal axis of the developing spinal cord. Wnts attract ascending axons via their seven-span transmembrane receptors, Frizzleds, and repel others via a different transmembrane receptor, Ryk, in the spinal cord. Our studies showed that the re-induced Wnt signaling system regulates the growth cone of axons in the injured adult central nervous system. Ryk-mediated Wnt repulsion causes the well-known retraction/die back of injured corticospinal tract axons and limits the regenerative potential of proprioceptive sensory axons even after conditioning lesion of their peripheral branches, whereby crushing the peripheral branch enhances the growth state of the central branch of sensory axons. This grant tests whether more effective regeneration can occur by combinatorial approaches. We will test whether combining Wnt signaling manipulation and PTEN deletion can further enhance the regenerative potential of conditioning lesion.